Vesicants were developed as chemical weapons to debilitate the military and civilian populations during World War-I/II as these chemicals cause rapid and severe painful inflammatory and blistering responses in the skin. These agents include mustards and arsenicals. Among them sulfur mustard and lewisite were weaponized as single agents as well as a mixture of the two. The only known antidote for arsenicals is British Anti-lewisite (BAL), which is not very effective and itself is highly toxic. The molecular pathogenesis of arsenicals remains poorly understood, which is also an important impediment in developing mechanism-based antidotes for mitigating the toxicity of these chemicals. Therefore, the major goal of this U54 Center is to develop mechanism-based highly efficacious antidotes against chemical war relevant arsenicals namely lewisite, diphenylchloroarsine, diphenylcynoarsine and diethylchloroarsine (as prioritized by the NIH CounterACT program). The scientific premise of this investigation lies in the strong and compelling preliminary data demonstrating that epigenetic regulation of molecular signaling pathways regulate arsenicals-mediated onset of aberrant and robust cutaneous inflammation and tissue damage. These data also indicate that recruitment of bromodomain 4 (BRD4) to promotor region of inducible genes could be involved in the pathogenesis of arsenicals-mediated multi-organ damage including skin, lung and kidney. To test this hypothesis, we have developed a murine model that recapitulates the tissue damaging acute as well as delayed responses of these arsenicals described in exposed humans. Three specific aims are proposed. In specific aim-1, studies are focused to fully characterize the animal model of arsenicals-mediated acute and delayed cutaneous, pulmonary and renal damage following skin exposure to these chemical vesicants. This will be achieved by defining molecular biomarkers and epigenetic marks associated with the progression of the damage. Specific aim-2 will define molecular mechanism of arsenicals' toxicity with an objective for developing novel mechanism-based pharmacological inhibitors that can mitigate arsenicals' toxicity including cutaneous, pulmonary and renal injury. Studies in specific aim-3 are related to defining window of effective therapeutic intervention of pharmacological inhibitors of BDR4 in terms of suppressing cutaneous, pulmonary and renal damage following skin exposure to these chemicals. The outcome of this study will lead to paradigm shift discovery of antidotes against arsenicals which could block effectively multi-organ damage, morbidity, and mortality. These inhibitors could also provide efficacy against other similar chemicals. In addition, based on the discovery of novel molecular targets, synthesis and characterization of small molecules will done by the Drug Discovery and Development Core. These antidotes could easily be delivered subcutaneously by auto-injectable FDA approved devices in case of mass causality. Thus these efforts will significantly enhance the medical response capabilities in tackling vesicants' exposure to public or soldiers in a terrorist attack or during chemical warfare.